We propose a longitudinal clinical, in vivo magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) study of three subject groups with clinical and MR evaluations at entry, 6, 12, 18, and 24 months. The subject groups are: probable Alzheimer's disease (AD) (N = 24, mildly demented at entry); Possible Dementia Prodrome (PDP) (N = 24); and age-matched controls (N = 24). Our previous 31P MRS studies of the prefrontal cortex of mildly demented probable AD subjects demonstrate increased membrane synthesis [increased phosphomonoesters (PME)] and increased energetic stress [decreased phosphocreatine (PCr)]. As the AD subjects progressed to moderate dementia, the PME levels decreased suggesting membrane degeneration and the PCr levels increased suggesting decreased utilization of PCr secondary to synaptic loss. The PME and PCr levels correlated with cognitive measures. In one presumed control, alterations in membrane and high-energy metabolites were evident several years before the onset of dementia. We hypothesize abnormal membrane synthesis occurs in PDP subjects who progress to probable AD and membrane degradation (including synaptic loss) occurs in moderately demented probable AD subjects. This study tests these hypotheses by using 31P-1H MRS chemical shift imaging to examine membrane phospholipid and high- energy phosphate metabolism and a measure of neuronal viability in 5 discrete brain regions including (both left and right) prefrontal, superior temporal and inferior parietal cortices as regions heavily involved in the pathophysiology of AD, the occipital cortex as a less involved primary sensory brain region, and the centrum semiovale as a representative white matter region. 1H MRl parameters of brain morphometry are obtained including grey and white matter volumes for total brain and for (both left and right) prefrontal, superior temporal, inferior parietal, and occipital cortices, and the hippocampus. We quantify the proportions of grey and white matter and CSF in voxels of interest identical to those from which MRS spectra are obtained. 31P-1H MRS metabolic parameters are compared with brain morphometry, cognitive parameters, and ApoE isoform type. Our studies indicate a recapitulation of neurodevelopmental events early in AD which could contribute to neurodegeneration. These studies should significantly add to our understanding of the pathophysiology of AD and aid in pre-symptomatic diagnosis.